Moreover, among the different protein phosphatases analyzed, binge drinking significantly stimulated NVP-BGJ398 ic50 the mRNA levels for PTPN1 by about 3-fold without an effect on PTPRA and PTPRF. Finally, to examine the causal role of IKKβ/NF-κB and PTPN1 induction by ethanol

on MBH insulin signaling impairment, small molecule inhibitors of both pathways, PS1145 and CTP-157633, respectively, were continuously infused into the lateral ventricle using osmotic minipumps. Forty-eight hours after pump implantation, rats were subjected to binge drinking and GTT was performed at 8, 30, and 54 hours after the last dose of ethanol. As expected, ethanol impaired glucose tolerance, and this effect persisted even up to 54 hours after the last ethanol dose. In contrast to the IKKβ inhibitor, pharmacological inhibition of central PTP1B improved glucose tolerance in ethanol-exposed rats at all timepoints examined, despite both inhibitors alleviated the hypothalamic inflammation Rapamycin purchase induced by binge drinking. These findings represent an important step forward to understand the deleterious effects of binge drinking on systemic insulin resistance and uncover a novel mechanism of action whereby ethanol impairs hypothalamic but not liver insulin signaling (Fig. 1). However, the study has several limitations and weaknesses. First of all, ethanol was given intraperitoneally. The rationale for intraperitoneal ethanol administration based on

the first-pass gastric metabolism was unclear, especially given

the relatively minor contribution of this process to overall ethanol metabolism. Moreover, as people abuse alcohol exclusively by oral intake the relevance of the “intraperitoneal binge drinking” effect on glucose homeostasis to the human situation is uncertain and deserves further investigation. In addition, the effect of binge drinking in increasing the PTPN1 mRNA level in MBH seems very modest (about 3-fold). Surprisingly, the authors did not show whether the transcriptional up-regulation medchemexpress of PTPN1 translated at the protein level, and, most important, if it resulted in enhanced PTPB1 activity. No evidence was provided that the efficacy of CPT-157633 in preventing ethanol-mediated impairment in insulin signaling in the MBH was associated with reduced PTPB1 activity. Of relevance, the possibility that CPT-157633 may have exerted off-target effects was not addressed by genetic targeting hypothalamic PTP1B (e.g., intracerebroventricular infusion of small interfering RNA [siRNA] into MBH). Moreover, the mechanisms whereby ethanol increased PTP1B expression were not addressed. In this regard, since ethanol is known to cause hepatic endoplasmic reticulum (ER) stress12 and in light of recent findings indicating that ER stress stimulates PTP1B expression,13 it is conceivable that binge drinking may have caused ER stress in the MBH, which may open up other therapeutic avenues to prevent the sequelae of ER stress, including PTP1B upregulation.